Current advances in gene therapy of mitochondrial diseases.

Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.

Cytokines in Abdominal Aortic Aneurysm: Master Regulators With Clinical Application.

Abdominal aortic aneurysm (AAA) is a potentially life-threatening disorder with a mostly asymptomatic course where the abdominal aorta is weakened and bulged. Cytokines play especially important roles (both positive and negative) among the molecular actors of AAA development. All the inflammatory cascades, extracellular matrix degradation and vascular smooth muscle cell apoptosis are driven by cytokines. Previous studies emphasize an altered expression and a changed epigenetic regulation of key cytokines in AAA tissue samples. Such cytokines as IL-6, IL-10, IL-12, IL-17, IL-33, IL-1ß, TGF-ß, TNF-α, IFN-γ, and CXCL10 seem to be crucial in AAA pathogenesis. Some data obtained in animal studies show a protective function of IL-10, IL-33, and canonical TGF-ß signaling, as well as a dual role of IL-4, IFN-γ and CXCL10, while TNF-α, IL-1ß, IL-6, IL-12/IL-23, IL-17, CCR2, CXCR2, CXCR4 and the TGF-ß noncanonical pathway are believed to aggravate the disease. Altogether data highlight significance of cytokines as informative markers and predictors of AAA. Pathologic serum/plasma concentrations of IL-1ß, IL-2, IL-6, TNF-α, IL-10, IL-8, IL-17, IFN-γ, and PDGF have been already found in AAA patients. Some of the changes correlate with the size of aneurysms. Moreover, the risk of AAA is associated with polymorphic variants of genes encoding cytokines and their receptors: CCR2 (rs1799864), CCR5 (Delta-32), IL6 (rs1800796 and rs1800795), IL6R (rs12133641), IL10 (rs1800896), TGFB1 (rs1800469), TGFBR1 (rs1626340), TGFBR2 (rs1036095, rs4522809, rs1078985), and TNFA (rs1800629). Finally, 5 single-nucleotide polymorphisms in gene coding latent TGF-ß-binding protein (LTBP4) and an allelic variant of TGFB3 are related to a significantly slower AAA annual growth rate.

Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern.

Recent studies have implicated synucleins in several reactions during the biosynthesis of lipids and fatty acids in addition to their recognised role in membrane lipid binding and synaptic functions. These are among aspects of decreased synuclein functions that are still poorly acknowledged especially in regard to pathogenesis in Parkinson's disease. Here, we aimed to add to existing knowledge of synuclein deficiency (i.e., the lack of all three family members), with respect to changes in fatty acids and lipids in plasma, liver, and two brain regions in triple synuclein-knockout (TKO) mice. We describe changes of long-chain polyunsaturated fatty acids (LCPUFA) and palmitic acid in liver and plasma, reduced triacylglycerol (TAG) accumulation in liver and non-esterified fatty acids in plasma of synuclein free mice. In midbrain, we observed counterbalanced changes in the relative concentrations of phosphatidylcholine (PC) and cerebrosides (CER). We also recorded a notable reduction in ethanolamine plasmalogens in the midbrain of synuclein free mice, which is an important finding since the abnormal ether lipid metabolism usually associated with neurological disorders. In summary, our data demonstrates that synuclein deficiency results in alterations of the PUFA synthesis, storage lipid accumulation in the liver, and the reduction of plasmalogens and CER, those polar lipids which are principal compounds of lipid rafts in many tissues. An ablation of all three synuclein family members causes more profound changes in lipid metabolism than changes previously shown to be associated with γ-synuclein deficiency alone. Possible mechanisms by which synuclein deficiency may govern the reported modifications of lipid metabolism in TKO mice are proposed and discussed.